Compositions and methods for treating nocturnal acid breakthrough and other related disorders

ABSTRACT

The present invention relates to, inter alia, pharmaceutical compositions comprising an acid labile proton pump inhibitor and a buffering agent; to methods for manufacture of such compositions, and to use of such compositions in treating and preventing diseases and/or disorders.

FIELD OF THE INVENTION

The present invention relates to, inter alia, pharmaceuticalcompositions comprising an acid labile proton pump inhibitor and abuffering agent; to methods for manufacture of such compositions, and touse of such compositions in treating and preventing diseases anddisorders including but not limited to nocturnal acid breakthrough andnighttime heartburn.

BACKGROUND OF THE INVENTION

Gastrointestinal disorders such as active duodenal ulcers, gastriculcers, gastroesophageal reflux disease (GERD), nocturnal acidbreakthrough, severe erosive esophagitis, poorly responsive symptomaticGERD, and pathological hypersecretory conditions such as ZollingerEllison syndrome represent a major health concern impacting millions ofpeople globally. In fact, it is estimated that as many as 60 millionAmericans alone experience acid reflux at least once a month, whileapproximately 19 million Americans suffer from GERD.

In the past, the above-described (and other related) gastrointestinaldisorders and their associated symptoms have been treated with H₂histamine antagonists and antacids. Unfortunately, many such availabletreatments are not very effective in ameliorating the disordersthemselves or their symptoms; additionally, many produce adverse sideeffects including, among others, constipation, diarrhea, andthrombocytopenia. Moreover, H₂ antagonists such as ranitidine andcimetidine are relatively costly modes of therapy generally requiringmultiple daily doses to produce some control of acid secretion. Inaddition, tolerance to H₂ antagonists increases with continued use thusprohibiting clinical utility in chronic dosing settings.

More recently, at least some of the above-described gastrointestinaldisorders have been treated with proton pump inhibitors (also calledPPIs). PPIs are believed to reduce gastric acid production by inhibitingH⁺, K⁺-ATPase of the parietal cell—the final common pathway for gastricacid secretion. One particular class of PPIs includes substitutedbenzimidazole compounds that contain a sulfinyl group bridgingsubstituted benzimidazole and pyridine rings.

At neutral pH, these PPIs are chemically stable, lipid-soluble compoundsthat have little or no inhibitory activity. It is believed that theneutral PPIs reach parietal cells from the blood and diffuse into thesecretory canaliculi where they become protonated and thereby trapped.The protonated agent is then believed to rearrange to form a sulfenicacid and a sulfenamide. The sulfenamide, in turn, is thought to interactcovalently with sulfhydryl groups at critical sites in the extracellular(luminal) domain of the membrane-spanning H⁺, K⁺-ATPase. See, Hardman etal., Goodman & Gilman's The Pharmacological Basis of Therapeutics, p.907, 9^(th) ed. (1996).

Unfortunately, most commercially available PPIs are unstable at neutralor acidic pH and undergo decomposition in gastrointestinal fluid uponoral administration, thereby resulting in loss of therapeutic activity.To overcome this acid instability, such compounds are typicallyformulated for oral delivery as enteric coated solid dosage forms, forexample enteric coated tablets; the enteric coating protects the drugfrom contact with acidic stomach secretions. An undesirable consequenceof such enteric coating is that therapeutic onset time is significantlydelayed by comparison with non-enteric coated dosage forms. Suchprolonged time to therapeutic onset is particularly undesirable forpatients in need of rapid relief from one or more of the above describeddisorders or symptoms.

For example, U.S. Pat. No. 4,786,505 to Lovgren et al. discloses that apharmaceutical oral solid dosage form of omeprazole must be protectedfrom contact with acidic gastric juice by an enteric coating to maintainits pharmaceutical activity. That patent describes an enteric coatedomeprazole preparation containing an alkaline core comprisingomeprazole, a subcoating over the core, and an enteric coating over thesubcoating.

Patients with GERD are typically given a once-daily dose of entericcoated PPI, administered in the morning, to manage daytime meal-inducedgastric acid secretion. However, normal gastric acid secretion follows acircadian rhythm, with gastric acid secretion being most pronounced inthe evening and early night. This results in a surge of gastric acidityaround 2:00 am, with acid secretion decreasing toward the later morning.See e.g. Moore, J. G., Englert E., Circadian rhythm of gastric acidsecretion in man. Nature 1970; 226: 1261-2 and Prewett, E. J., Smith, J.T., Nwokolo, C. U., et al., Twenty-four hour intragastric acidity andplasma gastrin concentration profiles in female and male subjects. Clin.Sci. (Lond) 1991; 80:619-24. Unfortunately, it is recognized thatcommercially available enteric coated proton pump inhibitors fail toadequately control nighttime gastric acid secretion and nighttime GERDsymptoms in many patients, regardless of when administered. For example,according to Tutuian R, et al., “[n]octurnal acid breakthrough occurs onany dosing regimen of oral proton pump inhibitors.” AlimentaryPharmacology & Therapeutics 2002; 16(3): 473-477. Furthermore, accordingto Katz P O, et al., “[n]octurnal acid breakthrough is frequently seenon proton pump inhibitors twice daily and is often accompanied byoesophageal reflux. This has important implications for medical therapyin patients with severe gastro-esophageal reflux and Barrett'soesophagus.” Gastro-oesophageal reflux associated with nocturnal gastricacid breakthrough on proton pump inhibitors. Alimentary Pharmacology &Therapeutics 1999; 12(12): 1231-1234.

Moreover, prolonged nocturnal esophageal acid exposure has been shown tocontribute to the development of erosive esophagitis. See, e.g. Orr, W.C., Allen, M. L., Robinson, M. The pattern of nocturnal and diurnalesophageal acid exposure in the pathogenesis of erosive mucosal damageAm J Gastroenterol. 1994 April; 89(4):509-12 and Hatlebakk, J. G.,Berstad, A. Endoscopic grading of reflux oesophagitis: what observationscorrelate with gastroesophogeal reflux? Scand. J. Gastroenterol. 1997;32:760-5.

Clearly, therefore, an unmet medical need exists for new formulations ofproton pump inhibitors that can treat nighttime acid breakthrough and/ornighttime heartburn and other acid related disorders.

SUMMARY OF THE INVENTION

In various embodiments, the present invention provides pharmaceuticalcompositions comprising at least one acid labile proton pump inhibitorand at least one buffering agent. Also provided are methods of treatingand/or preventing acid related gastrointestinal disorders byadministering to a subject one or more compositions of the invention. Inone embodiment, methods are provided for treating and/or preventingnighttime acid breakthrough and/or nighttime heartburn and relatedsymptoms thereof.

DETAILED DESCRIPTION OF THE INVENTION

While the present invention is capable of being embodied in variousforms, the description below of several embodiments is made with theunderstanding that the present disclosure is to be considered as anexemplification of the invention, and is not intended to limit theinvention to the specific embodiments illustrated. Headings are providedfor convenience only and are not to be construed to limit the inventionin any way. Embodiments illustrated under any heading may be combinedwith embodiments illustrated under any other heading.

The use of numerical values in the various ranges specified in thisapplication, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges were both preceded by the word “about.” In this manner,slight variations above and below the stated ranges can be used toachieve substantially the same results as values within the ranges. Asused herein, the terms “about” and “approximately” when referring to anumerical value shall have their plain and ordinary meanings to oneskilled in the art of pharmaceutical sciences or the art relevant to therange or element at issue. The amount of broadening from the strictnumerical boundary depends upon many factors. For example, some of thefactors to be considered may include the criticality of the elementand/or the effect a given amount of variation will have on theperformance of the claimed subject matter, as well as otherconsiderations known to those of skill in the art. Thus, as a generalmatter, “about” or “approximately” broaden the numerical value. Forexample, in some cases, “about” or “approximately” may mean ±5%, or±10%, or ±20%, or ±30% depending on the relevant technology. Also, thedisclosure of ranges is intended as a continuous range including everyvalue between the minimum and maximum values recited as well as anyranges that can be formable thereby.

It is also to be understood that any ranges, ratios and ranges of ratiosthat can be formed by any of the numbers or data present hereinrepresent further embodiments of the present invention. This includesranges that can be formed that do or do not include a finite upperand/or lower boundary. For example, by way of illustration and notlimitation, in one embodiment, a proton pump inhibitor is present in acomposition of the invention in an amount of about 1 to about 3000 mg;in another embodiment, a buffering agent is present in a composition ofthe invention in an amount of about 200 mg to about 3500 mg. One ofskill in the art will therefore recognize, for example, that additionalembodiments include situations where a composition has a PPI:bufferingagent weight ratio of less than or greater than 1:200, less than orgreater than about 1:3500, less than or greater than 15:1 (3000/200), orless than or greater than about 0.85 (3000:3500), or in ranges of about1:200 to about 1:3500, about 1:3500 to about 15:1, etc. Accordingly, theskilled person will appreciate that many such ratios, ranges, and rangesof ratios can be unambiguously derived from the data and numberspresented herein and all represent embodiments of the present invention.

Proton Pump Inhibitors

Compositions of the invention comprise at least one pharmaceuticallyacceptable acid labile PPI, for example a substituted imidazole,tetrabenzimidazole, or benzimidazole H⁺,K⁺-ATPase PPI. The term protonpump inhibitor or PPI means any acid labile pharmaceutical agentpossessing pharmacological activity as an inhibitor of H+/K+-ATPase. APPI may, if desired, be in the form of free base, free acid, salt,ester, hydrate, anhydrate, amide, enantiomer, isomer, tautomer, prodrug,polymorph, derivative, or the like, provided that the free base, salt,ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug, or anyother pharmacologically suitable derivative is therapeutically active orundergoes conversion within or outside of the body to a therapeuticallyactive form.

In one embodiment, illustrative PPIs are those compounds of Formula (I):

wherein

R¹ is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy,carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy which isoptionally fluorinated, hydroxyalkyl, trifluoromethyl, acyl,carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, oralkylsulfinyl;

R² is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino, aralkyl,carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl;

R³ and R⁵ are the same or different and each is hydrogen, alkyl, C₁₋₄lower alkyl (e.g. methyl, ethyl, etc.), alkoxy, amino, or alkoxyalkoxy;

R⁴ is hydrogen, alkyl, C₁₋₄ lower alkyl (e.g. methyl, ethyl, etc.),alkoxy which may optionally be fluorinated, or alkoxyalkoxy;

Q is nitrogen, CH, or CR¹;

W is nitrogen, CH, or CR¹;

y is an integer of 0 through 4; and

Z is nitrogen, CH, or CR¹;

or a free base, salt, ester, hydrate, amide, enantiomer, isomer,tautomer, prodrug, polymorph, or derivative thereof.

Specific examples of suitable PPIs include esomeprazole (also referredto as S-omeprazole), ilaprazole (U.S. Pat. No. 5,703,097), lansoprazole,omeprazole, pantoprazole, pariprazole, rabeprazole, tenatoprazole,leminoprazole and nepaprazole or a free base, a free acid, or a salt,hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug,or derivative of such compounds.

Other proton pump inhibitors include but are not limited to: soraprazan(Altana); AZD-0865 (AstraZeneca); YH-1885 (PCT Publication WO 96/05177)(SB-641257) (2-pyrimidinamine,4-(3,4-dihydro-1-methyl-2(1H)-isoquinolinyl)-N-(4-fluo-rophenyl)-5,6-dimethyl-monohydrochloride)(YuHan); BY-112 (Altana); SPI-447(Imidazo[1,2-a]thieno(3,2-c)pyridin-3-amine,5-methyl-2-(2-methyl-3-thieny-1) (Shinnippon);3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrano(2,-3-c)-imidazo[1,2-a]pyridine(PCT Publication WO 95/27714) (AstraZeneca); Pharmaprojects No. 4950(3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-1-pyrano(2,3-c)-imidazo[1,2-a]pyridine)(AstraZeneca, ceased) WO 95/27714; Pharmaprojects No. 4891 (EP 700899)(Aventis); Pharmaprojects No. 4697 (PCT Publication WO 95/32959)(AstraZeneca); H-335/25 (AstraZeneca); T-330 (Saitama 335)(Pharmacological Research Lab); Pharmaprojects No. 3177 (Roche); BY-574(Altana); Pharmaprojects No. 2870 (Pfizer); AU-1421 (EP 264883) (Merck);AU-2064 (Merck); AY-28200 (Wyeth); Pharmaprojects No. 2126 (Aventis);WY-26769 (Wyeth); pumaprazole (PCT Publication WO 96/05199) (Altana);YH-1238 (YuHan); Pharmaprojects No. 5648 (PCT Publication WO 97/32854)(Dainippon); BY-686 (Altana); YM-020 (Yamanouchi); GYKI-34655 (Ivax);FPL-65372 (Aventis); Pharmaprojects No. 3264 (EP 509974) (AstraZeneca);nepaprazole (To a Eiyo); HN-11203 (Nycomed Pharma); OPC-22575;pumilacidin A (BMS); saviprazole (EP 234485) (Aventis); SK and F-95601(GSK, discontinued); Pharmaprojects No. 2522 (EP 204215) (Pfizer);S-3337 (Aventis); RS-13232A (Roche); AU-1363 (Merck); SK and F-96067 (EP259174) (Altana); SUN 8176 (Daiichi Pharma); Ro-18-5362 (Roche);ufiprazole (EP 74341) (AstraZeneca); and Bay-p-1455 (Bayer); or a freebase, free acid, salt, hydrate, ester, amide, enantiomer, isomer,tautomer, polymorph, prodrug, or derivative of these compounds.

Still other proton pump inhibitors contemplated by the present inventioninclude those described in the following U.S. Pat. Nos. 4,628,098;4,689,333; 4,786,505; 4,853,230; 4,965,269; 5,021,433; 5,026,560;5,045,321; 5,093,132; 5,430,042; 5,433,959; 5,576,025; 5,639,478;5,703,110; 5,705,517; 5,708,017; 5,731,006; 5,824,339; 5,855,914;5,879,708; 5,948,773; 6,017,560; 6,123,962; 6,187,340; 6,296,875;6,319,904; 6,328,994; 4,255,431; 4,508,905; 4,636,499; 4,738,974;5,690,960; 5,714,504; 5,753,265; 5,817,338; 6,093,734; 6,013,281;6,136,344; 6,183,776; 6,328,994; 6,479,075; 6,559,167.

Proton pump inhibitors as well as their salts, hydrates, esters, amides,enantiomers, isomers, tautomers, polymorphs, prodrugs, and derivativesmay be prepared using standard procedures known to those skilled in theart of synthetic organic chemistry. See, e.g., March, Advanced OrganicChemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York:Wiley-Interscience, 1992); Leonard et al., Advanced Practical OrganicChemistry (1992); Howarth et al., Core Organic Chemistry (1998); andWeisermel et al., Industrial Organic Chemistry (2002).

“Pharmaceutically acceptable salts,” or “salts,” include the salt of aproton pump inhibitor prepared from formic, acetic, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic,phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic,benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic,sulfanilic, cyclohexylaminosulfonic, algenic, beta.-hydroxybutyric,galactaric and galacturonic acids.

In one embodiment, acid addition salts are prepared from the free baseforms using conventional methodology involving reaction of the free basewith a suitable acid. Suitable acids for preparing acid addition saltsinclude both organic acids, e.g., acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, p-toluenesulfonic acid, salicylic acid, and the like, as well asinorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like.

In other embodiments, an acid addition salt is reconverted to the freebase by treatment with a suitable base. In a further embodiment, theacid addition salts of the proton pump inhibitors are halide salts,which are prepared using hydrochloric or hydrobromic acids. In stillother embodiments, the basic salts are alkali metal salts, e.g., sodiumsalt.

Salt forms of proton pump inhibitors include, but are not limited to: asodium salt form such as esomeprazole sodium, omeprazole sodium,rabeprazole sodium, pantoprazole sodium; or a magnesium salt form suchas esomeprazole magnesium or omeprazole magnesium, described in U.S.Pat. No. 5,900,424; a calcium salt form; or a potassium salt form suchas the potassium salt of esomeprazole, described in U.S. Pat. No.6,511,996. Other salts of esomeprazole are described in U.S. Pat. Nos.4,738,974 and 6,369,085. Salt forms of pantoprazole and lansoprazole arediscussed in U.S. Pat. Nos. 4,758,579 and 4,628,098, respectively.

In one embodiment, preparation of esters involves functionalizinghydroxyl and/or carboxyl groups that may be present within the molecularstructure of the drug. In another embodiment, the esters areacyl-substituted derivatives of free alcohol groups, e.g., moietiesderived from carboxylic acids of the formula RCOOR₁ where ₁ is a loweralkyl group. Esters can be reconverted to the free acids, if desired, byusing conventional procedures such as hydrogenolysis or hydrolysis.

“Amides” may be prepared using techniques known to those skilled in theart or described in the pertinent literature. For example, amides may beprepared from esters, using suitable amine reactants, or they may beprepared from an anhydride or an acid chloride by reaction with an aminegroup such as ammonia or a lower alkyl amine.

“Tautomers” of substituted bicyclic aryl-imidazoles include, e.g.,tautomers of omeprazole such as those described in U.S. Pat. Nos.6,262,085; 6,262,086; 6,268,385; 6,312,723; 6,316,020; 6,326,384;6,369,087; and 6,444,689.

An exemplary “isomer” of a substituted bicyclic aryl-imidazole is theisomer of omeprazole including but not limited to isomers described in:Oishi et al., Acta Cryst. (1989), C45, 1921-1923; U.S. Pat. No.6,150,380; U.S. Patent Publication No. 02/0156284; and PCT PublicationNo. WO 02/085889.

Exemplary “polymorphs” include, but are not limited to, those describedin PCT Publication No. WO 92/08716, and U.S. Pat. Nos. 4,045,563;4,182,766; 4,508,905; 4,628,098; 4,636,499; 4,689,333; 4,758,579;4,783,974; 4,786,505; 4,808,596; 4,853,230; 5,026,560; 5,013,743;5,035,899; 5,045,321; 5,045,552; 5,093,132; 5,093,342; 5,433,959;5,464,632; 5,536,735; 5,576,025; 5,599,794; 5,629,305; 5,639,478;5,690,960; 5,703,110; 5,705,517; 5,714,504; 5,731,006; 5,879,708;5,900,424; 5,948,773; 5,997,903; 6,017,560; 6,123,962; 6,147,103;6,150,380; 6,166,213; 6,191,148; 5,187,340; 6,268,385; 6,262,086;6,262,085; 6,296,875; 6,316,020; 6,328,994; 6,326,384; 6,369,085;6,369,087; 6,380,234; 6,428,810; 6,444,689; and 6,462,0577.

In one embodiment, no portion of the proton pump inhibitor is entericcoated. In another embodiment, at least a portion of the proton pumpinhibitor is not enteric coated. In another embodiment, at least atherapeutically effective portion of the proton pump inhibitor is notenteric coated. In another embodiment, at least about 5%, about 15%,about 20%, about 30%, about 40%, about 50% or about 60% of the protonpump inhibitor is not enteric coated.

In one embodiment, the proton pump inhibitor has a D₉₀, D₈₀, D₇₀ or D₅₀particle size, by weight or by number, of less than about 500 μm, lessthan about 400 μm, less than about 300 μm, less than about 200 μm, lessthan about 150 μm, less than about 100 μm, less than about 80 μm, lessthan about 60 μm, less than about 40 μm, less than about 35 μm, lessthan about 30 μm, less than about 25 μm, less than about 20 μm, lessthan about 15 μm, or less than about 10 μm.

In another embodiment, compositions are provided wherein the micronizedproton pump inhibitor is of a size which allows greater than about 90%or greater than about 75% of the proton pump inhibitor to be releasedfrom the dosage unit within about 1 hour, within about 50 minutes,within about 40 minutes, within about 30 minutes, within about 20minutes, within about 10 minutes, or within about 5 minutes afterplacement in a standard dissolution test.

In another embodiment, compositions of the invention comprise one ormore PPIs in a total amount of about 1 mg to about 3000 mg, about 1 mgto about 2000 mg, about 1 mg to about 1000 mg, about 5 mg to about 750mg, about 5 mg to about 500 mg, about 5 mg to about 250 mg, about 5 mgto about 100 mg, about 5 mg to about 100 mg, or about 5 mg to about 50mg, for example about 7.5 mg, about 10 mg, about 15 mg, about 20 mg orabout 40 mg.

Compositions of the invention can be in the form of an orallydeliverable dosage unit. The terms “oral administration” or “orallydeliverable” herein include any form of delivery of a therapeutic agentor a composition thereof to a subject wherein the agent or compositionis placed in the mouth of the subject, whether or not the agent orcomposition is swallowed. Thus “oral administration” includes buccal andsublingual as well as esophageal administration.

Buffering Agent

Compositions of the invention comprise one or more pharmaceuticallyacceptable buffering agents. Buffering agents useful in the presentinvention include agents possessing pharmacological activity as a weakor strong base. In one embodiment, the buffering agent, when formulatedwith or administered substantially simultaneously with a PPI, functionsto raise the pH of gastrointestinal fluid and thereby to substantiallyprevent or inhibit acid degradation of the PPI by gastrointestinal fluidfor a period of time. In one embodiment, the period of time is a timesufficient to protect at least a therapeutic portion of the PPI fromacid degradation in GI fluid.

In another embodiment, buffering agents useful in accordance with thepresent invention comprise a salt of a Group IA metal including, forexample, a bicarbonate salt of a Group IA metal, a carbonate salt of aGroup IA metal, an alkaline earth metal buffering agent, an amino acid,an alkaline salt of an amino acid, an aluminum buffering agent, acalcium buffering agent, a sodium buffering agent, or a magnesiumbuffering agent. Other suitable buffering agents include alkali (sodiumand potassium) or alkaline earth (calcium and magnesium) carbonates,phosphates, bicarbonates, citrates, borates, acetates, phthalates,tartrates, succinates and the like, such as sodium or potassiumphosphate, citrate, borate, acetate, bicarbonate and carbonate.

Non-limiting examples of suitable buffering agents include aluminum,magnesium hydroxide, aluminum hydroxide/magnesium hydroxideco-precipitate, aluminum hydroxide/sodium bicarbonate co-precipitate,aluminum glycinate, calcium acetate, calcium bicarbonate, calciumborate, calcium carbonate, calcium citrate, calcium gluconate, calciumglycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate,calcium phosphate, calcium succinate, calcium tartrate, dibasic sodiumphosphate, dipotassium hydrogen phosphate, dipotassium phosphate,disodium hydrogen phosphate, disodium succinate, dry aluminum hydroxidegel, L-arginine, magnesium acetate, magnesium aluminate, magnesiumborate, magnesium bicarbonate, magnesium carbonate, magnesium citrate,magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesiummetasilicate aluminate, magnesium oxide, magnesium phthalate, magnesiumphosphate, magnesium silicate, magnesium succinate, magnesium tartrate,potassium acetate, potassium carbonate, potassium bicarbonate, potassiumborate, potassium citrate, potassium metaphosphate, potassium phthalate,potassium phosphate, potassium polyphosphate, potassium pyrophosphate,potassium succinate, potassium tartrate, sodium acetate, sodiumbicarbonate, sodium borate, sodium carbonate, sodium citrate, sodiumgluconate, sodium hydrogen phosphate, sodium hydroxide, sodium lactate,sodium phthalate, sodium phosphate, sodium polyphosphate, sodiumpyrophosphate, sodium sesquicarbonate, sodium succinate, sodiumtartrate, sodium tripolyphosphate, synthetic hydrotalcite,tetrapotassium pyrophosphate, tetrasodium pyrophosphate, tripotassiumphosphate, trisodium phosphate, and trometarnol. (Based in part upon thelist provided in The Merck Index, Merck & Co. Rahway, N.J. (2001)). Inaddition, due to the ability of proteins or protein hydrolysates toreact with stomach acids, they too can serve as buffering agents in thepresent invention. Furthermore, combinations or mixtures of the abovementioned buffering agents can be used in the pharmaceuticalformulations described herein.

Buffering agents useful in the present invention also include bufferingagents or combinations of buffering agents that interact with HCl (orother acids in the environment of interest) faster than the proton pumpinhibitor interacts with the same acids. When placed in a liquid phasesuch as water, these buffering agents produce and maintain a pH greaterthan the pKa of the proton pump inhibitor.

In various other embodiments of the present invention, the bufferingagent is present in a total amount of about 0.1 mEq/mg to about 5 mEq/mgof the proton pump inhibitor, about 0.5 mEq/mg to about 3 mEq/mg of theproton pump inhibitor, about 0.6 mEq/mg to about 2.5 mEq/mg of theproton pump inhibitor, about 0.7 mEq/mg to about 2.0 mEq/mg of theproton pump inhibitor, about 0.8 mEq/mg to about 1.8 mEq/mg of theproton pump inhibitor, about 1.0 mEq/mg to about 1.5 mEq/mg of theproton pump inhibitor. In another embodiment, the buffering agent ispresent in an amount of at least about 0.5 mEq/mg of the proton pumpinhibitor, at least about 0.75 mEq/mg of the proton pump inhibitor, orat least about 1 mEq/mg of the proton pump inhibitor on a dry weightbasis.

In another embodiment, one or more buffering agents are present in atotal amount of about 0.5 mEq to about 160 mEq, about 1 mEq to about 150mEq, about 10 mEq to about 150 mEq, about 10 mEq to about 75 mEq, about10 mEq to about 60 mEq, or about 10 mEq to about 50 mEq. Illustratively,a composition of the invention can comprise about 1 mEq, or about 5 mEq,or about 10 mEq, or about 15 mEq, or about 20 mEq, or about 25 mEq, orabout 30 mEq, or about 35 mEq, or about 40 mEq, or about 45 mEq, orabout 50 mEq, or about 60 mEq, or about 70 mEq, or about 80 mEq, orabout 90 mEq, or about 100 mEq, or about 110 mEq, or about 120 mEq, orabout 130 mEq, or about 140 mEq, or about 150 mEq, or about 160 mEq ofbuffering agent.

In yet another embodiment, one or more buffering agents are present in atotal amount of at least about 10 mEq, at least about 11 mEq, at leastabout 12 mEq, at least about 13 mEq, at least about 14 mEq, or at leastabout 15 mEq.

In still another embodiment, one or more buffering agents and the PPIare present in a weight ratio of at least about 5:1, at least about 7:1,at least about 10:1, at least about 20:1, greater than 20:1, at leastabout 21:1, at least about 22:1, at least about 23:1, at least about25:1, at least about 30:1, at least about 35:1, at least about 40:1,greater than 40:1, or at least about 45:1.

In another embodiment, the amount of buffering agent present in acomposition of the invention ranges from about 200 to about 3500 mg,about 300 to about 3000 mg, about 400 to about 2500 mg, or about 500 toabout 2200 mg. In other embodiments, the amount of buffering agentpresent in a composition of the invention is about 200 mgs, or about 300mgs, or about 400 mgs, or about 500 mgs, or about 600 mgs, or about 700mgs, or about 800 mgs, or about 900 mgs, or about 1000 mgs, or about1100 mgs, or about 1200 mgs, or about 1300 mgs, or about 1400 mgs, orabout 1500 mgs, or about 1600 mgs, or about 1700 mgs, or about 1800 mgs,or about 1900 mgs, or about 2000 mgs, or about 2100 mgs, or about 2200mgs, or about 2300 mgs, or about 2400 mgs, or about 2500 mgs, or about2600 mgs, or about 2700 mgs, or about 2800 mgs, or about 2900 mgs, orabout 3000 mgs, or about 3200 mgs, or about 3500 mgs.

In another embodiment, one or more buffering agents are present in acomposition of the invention in a total amount that is greater than 800mg, for example at least about 920 mg or at least about 1000 mg.

In still another embodiment, particularly where the composition is otherthan a dosage form selected from the group consisting of a suspensiontablet, a chewable tablet, an effervescent powder, an effervescenttablet, lozenge and/or a troche, the buffering agent and PPI are presentin a weight ratio greater than 20:1, not less than about 21:1, not lessthan about 22:1, not less than about 23:1, not less than about 24:1, notless than about 25:1, not less than about 26:1, not less than about27:1, not less than about 28:1, not less than about 29:1, not less thanabout 30:1, not less than about 31:1, not less than about 32:1, not lessthan about 33:1, not less than about 34:1, not less than about 35:1, notless than about 36:1, not less than about 37:1, not less than about38:1, not less than about 39:1, not less than about 40:1, not less thanabout 41:1, not less than about 42:1, not less than about 43:1, not lessthan about 44:1, not less than about 45:1, not less than about 46:1, notless than about 47:1, not less than about 48:1, not less than about49:1, or not less than about 50:1.

In another embodiment, a composition is provided that comprises acombination of at least two non-amino acid buffering agents, wherein thecombination of at least two non-amino acid buffering agents comprisessubstantially no aluminum hydroxide-sodium bicarbonate co-precipitate.In a related embodiment, if such a composition comprises apoly[phosphoryl/sulfon]-ated carbohydrate, the weight ratio ofpoly[phosphoryl/sulfon]-ated carbohydrate to buffering agent is lessthan 1:5 (0.2), less than 1:10 (0.1) or less than 1:20 (0.05).Alternatively, the poly[phosphoryl/sulfon]-ated carbohydrate is presentin the composition, if at all, in an amount less than 50 mg, less than25 mg, less than 10 mg or less than 5 mg.

In other embodiments, if the pharmaceutical composition comprises anamino acid buffering agent, the total amount of amino acid bufferingagent present in the pharmaceutical composition is less than about 5mEq, or less than about 4 mEq, or less than about 3 mEq.

The phrase “amino acid buffering agent” as used herein includes aminoacids, amino acid salts, and amino acid alkali salts including: glycine,alanine, threonine, isoleucine, valine, phenylalanine, glutamic acid,asparagininic acid, lysine, aluminum glycinate and/or lysine glutamicacid salt, glycine hydrochloride, L-alanine, DL-alanine, L-threonine,DL-threonine, L-isoleucine, L-valine, L-phenylalanine, L-glutamic acid,L-glutamic acid hydrochloride, L-glutamic acid sodium salt,L-asparaginic acid, L-asparaginic acid sodium salt, L-lysine andL-lysine-L-glutamic acid salt. The term “non-amino acid buffering agent”herein includes buffering agents as defined hereinabove but does notinclude amino acid buffering agents.

In another embodiment, a composition of the invention comprises at leastone non-amino acid buffering agent wherein the non-amino acid bufferingagent is present in the composition in a total amount greater than 800mg. In a related embodiment, if such a composition comprises apoly[phosphoryl/sulfon]-ated carbohydrate, the weight ratio ofpoly[phosphoryl/sulfon]-ated carbohydrate to buffering agent is lessthan 1:5 (0.2), less than 1:10 (0.1) or less than 1:20 (0.05).Alternatively, the poly[phosphoryl/sulfon]-ated carbohydrate is presentin the composition, if at all, in an amount less than 50 mg, less than25 mg, less than 10 mg or less than 5 mg.

In still another embodiment, a composition is provided which comprisesat least one buffering agent in a total amount of at least about 10 mEq.In a related embodiment, if an amino acid buffering agent is present inthe composition, at least one of the following conditions is met: (1)the weight ratio of amino acid buffering agent:proton pump inhibitor isgreater than 20:1; (2) the composition comprises at least two non-aminoacid buffering agents; (3) the composition comprises at least onenon-amino acid buffering agent wherein the weight ratio of the at leastone non-amino acid buffering agent:proton pump inhibitor is greater than20:1; and/or (4) the weight ratio of total buffering agent:proton pumpinhibitor is greater than 40:1.

In other embodiments, where two or more buffering agents are present,the two or more buffering agents comprise at least two non-amino acidbuffering agents, wherein the combination of at least two non-amino acidbuffering agents comprises substantially no aluminum hydroxide-sodiumbicarbonate co-precipitate.

In still another embodiment, the buffering agent comprises a mixture ofsodium bicarbonate, calcium carbonate, and magnesium hydroxide, whereinthe sodium bicarbonate, calcium carbonate, and magnesium hydroxide areeach present in an amount of about 0.1 mEq/mg proton pump inhibitor toabout 5 mEq/mg of the proton pump inhibitor.

Also provided herein are pharmaceutical compositions comprising at leastone soluble buffering agent. The term “soluble buffering agent” as usedherein refers to an antacid that has a solubility of at least about 500mg/mL, or at least about 300 mg/mL, or at least about 200 mg/mL, or atleast about 100 mL/mL in gastrointestinal fluid or simulatedgastrointestinal fluid.

In some embodiments of the present invention, the buffering agent has adefined particle size distribution. For example, in one embodiment, theD₅₀, D₇₀, D₈₀, or D₉₀ particle size of the buffering agent, by weight orby number, is no greater than about 20 μm, no greater than about 30 μm,no greater than about 40 μm, no greater than about 50 μm, no greaterthan about 60 μm, no greater than about 70 μm, no greater than about 80μm, no greater than about 90 μm, no greater than about 100 μm indiameter, no greater than about 200 μm in diameter, no greater thanabout 300 μm in diameter, no greater than about 400 μm in diameter, orno greater than about 100 μm in diameter.

Pharmaceutical Excipients

Compositions of the invention can, if desired, include one or morepharmaceutically acceptable excipients. The term “excipient” hereinmeans any substance, not itself a therapeutic agent, used as a carrieror vehicle for delivery of a therapeutic agent to a subject or added toa pharmaceutical composition to improve its handling or storageproperties or to permit or facilitate formation of a dose unit of thecomposition. Excipients include, by way of illustration and notlimitation, diluents, disintegrants, binding agents, adhesives, wettingagents, lubricants, glidants, surface modifying agents, substances addedto mask or counteract a disagreeable taste or odor, flavors, dyes,fragrances, and substances added to improve appearance of thecomposition. Any such excipients can be used in any dosage forms ofaccording to the present invention, including liquid, solid orsemi-solid dosage forms.

Excipients optionally employed in compositions of the invention can besolids, semi-solids, liquids or combinations thereof. Compositions ofthe invention containing excipients can be prepared by any knowntechnique of pharmacy that comprises admixing an excipient with a drugor therapeutic agent.

Compositions of the invention optionally comprise one or morepharmaceutically acceptable diluents as excipients. Suitable diluentsillustratively include, either individually or in combination, lactose,including anhydrous lactose and lactose monohydrate; starches, includingdirectly compressible starch and hydrolyzed starches (e.g., Celutab™ andEmdex™); mannitol; sorbitol; xylitol; dextrose (e.g., Cerelose™ 2000)and dextrose monohydrate; dibasic calcium phosphate dihydrate;sucrose-based diluents; confectioner's sugar; monobasic calcium sulfatemonohydrate; calcium sulfate dihydrate; granular calcium lactatetrihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose;celluloses including microcrystalline cellulose, food grade sources ofα- and amorphous cellulose (e.g., Rexcel™) and powdered cellulose;calcium carbonate; glycine; bentonite; polyvinylpyrrolidone; and thelike. Such diluents, if present, constitute in total about 5% to about99%, about 10% to about 85%, or about 20% to about 80%, of the totalweight of the composition. The diluent or diluents selected preferablyexhibit suitable flow properties and, where tablets are desired,compressibility.

The use of extragranular microcrystalline cellulose (that is,microcrystalline cellulose added to a wet granulated composition after adrying step) can be used to improve hardness (for tablets) and/ordisintegration time.

Compositions of the invention optionally comprise one or morepharmaceutically acceptable disintegrants as excipients, particularlyfor tablet formulations. Suitable disintegrants include, eitherindividually or in combination, starches, including sodium starchglycolate (e.g., Explotab™ of PenWest) and pregelatinized corn starches(e.g., National™ 1551, National™ 1550, and Colocorn™ 1500), clays (e.g.,Veegum™ HV), celluloses such as purified cellulose, microcrystallinecellulose, methylcellulose, carboxymethylcellulose and sodiumcarboxymethylcellulose, croscarmellose sodium (e.g., Ac-Di-Sol™ of FMC),alginates, crospovidone, and gums such as agar, guar, xanthan, locustbean, karaya, pectin and tragacanth gums.

Disintegrants may be added at any suitable step during the preparationof the composition, particularly prior to a granulation step or during alubrication step prior to compression. Such disintegrants, if present,constitute in total about 0.2% to about 30%, about 0.2% to about 10%, orabout 0.2% to about 5%, of the total weight of the composition.

Croscarmellose sodium is a preferred disintegrant for tablet or capsuledisintegration, and, if present, typically constitutes about 0.2% toabout 10%, about 0.2% to about 7%, or about 0.2% to about 5%, of thetotal weight of the composition.

Compositions of the invention optionally comprise one or morepharmaceutically acceptable binding agents or adhesives as excipients,particularly for tablet formulations. Such binding agents and adhesivespreferably impart sufficient cohesion to the powder being tableted toallow for normal processing operations such as sizing, lubrication,compression and packaging, but still allow the tablet to disintegrateand the composition to be absorbed upon ingestion. Suitable bindingagents and adhesives include, either individually or in combination,acacia; tragacanth; sucrose; gelatin; glucose; starches such as, but notlimited to, pregelatinized starches (e.g., National™ 1511 and National™1500); celluloses such as, but not limited to, methylcellulose andcarmellose sodium (e.g., Tylose™); alginic acid and salts of alginicacid; magnesium aluminum silicate; PEG; guar gum; polysaccharide acids;bentonites; povidone, for example povidone K-15, K-30 and K-29/32;polymethacrylates; HPMC; hydroxypropylcellulose (e.g., Klucel™); andethylcellulose (e.g., Ethocel™). Such binding agents and/or adhesives,if present, constitute in total about 0.5% to about 25%, about 0.75% toabout 15%, or about 1% to about 10%, of the total weight of thecomposition.

Compositions of the invention optionally comprise one or morepharmaceutically acceptable wetting agents as excipients. Non-limitingexamples of surfactants that can be used as wetting agents incompositions of the invention include quaternary ammonium compounds, forexample benzalkonium chloride, benzethonium chloride and cetylpyridiniumchloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenylethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9,poloxamers (polyoxyethylene and polyoxypropylene block copolymers),polyoxyethylene fatty acid glycerides and oils, for examplepolyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g.,Labrasol™ of Gattefosse), polyoxyethylene (35) castor oil andpolyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkylethers, for example polyoxyethylene (20) cetostearyl ether,polyoxyethylene fatty acid esters, for example polyoxyethylene (40)stearate, polyoxyethylene sorbitan esters, for example polysorbate 20and polysorbate 80 (e.g., Tween™ 80 of ICI), propylene glycol fatty acidesters, for example propylene glycol laurate (e.g., Lauroglycol™ ofGattefosse), sodium lauryl sulfate, fatty acids and salts thereof, forexample oleic acid, sodium oleate and triethanolamine oleate, glycerylfatty acid esters, for example glyceryl monostearate, sorbitan esters,for example sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate and sorbitan monostearate, tyloxapol, and mixturesthereof. Such wetting agents, if present, constitute in total about0.25% to about 15%, about 0.4% to about 10%, or about 0.5% to about 5%,of the total weight of the composition.

Compositions of the invention optionally comprise one or morepharmaceutically acceptable lubricants (including anti-adherents and/orglidants) as excipients. Suitable lubricants include, eitherindividually or in combination, glyceryl behapate (e.g., Compritol™888); stearic acid and salts thereof, including magnesium (magnesiumstearate), calcium and sodium stearates; hydrogenated vegetable oils(e.g., Sterotex™); colloidal silica; talc; waxes; boric acid; sodiumbenzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine;PEG (e.g., Carbowax™ 4000 and Carbowax™ 6000); sodium oleate; sodiumlauryl sulfate; and magnesium lauryl sulfate. Such lubricants, ifpresent, constitute in total about 0.1% to about 10%, about 0.2% toabout 8%, or about 0.25% to about 5%, of the total weight of thecomposition.

Suitable anti-adherents include talc, cornstarch, DL-leucine, sodiumlauryl sulfate and metallic stearates. Talc is a anti-adherent orglidant used, for example, to reduce formulation sticking to equipmentsurfaces and also to reduce static in the blend. Talc, if present,constitutes about 0.1% to about 10%, about 0.25% to about 5%, or about0.5% to about 2%, of the total weight of the composition.

Glidants can be used to promote powder flow of a solid formulation.Suitable glidants include colloidal silicon dioxide, starch, talc,tribasic calcium phosphate, powdered cellulose and magnesiumtrisilicate. Colloidal silicon dioxide is particularly preferred.

Compositions of the present invention can comprise one or moreanti-foaming agents. Simethicone is an illustrative anti-foaming agent.

Compositions of the present invention can comprise one or more flavoringagents, sweetening agents, and/or colorants. Flavoring agents useful inthe present invention include, without limitation, acacia syrup,alitame, anise, apple, aspartame, banana, Bavarian cream, berry, blackcurrant, butter, butter pecan, butterscotch, calcium citrate, camphor,caramel, cherry, cherry cream, chocolate, cinnamon, citrus, citruspunch, citrus cream, cocoa, coffee, cola, cool cherry, cool citrus,cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruitpunch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape,grapefruit, honey, isomalt, lemon, lime, lemon cream, MagnaSweet®,maltol, mannitol, maple, menthol, mint, mint cream, mixed berry, nut,orange, peanut butter, pear, peppermint, peppermint cream, Prosweet®Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol,spearmint, spearmint cream, strawberry, strawberry cream, stevia,sucralose, sucrose, Swiss cream, tagatose, tangerine, thaumatin, tuttifruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol,and combinations thereof, for example, anise-menthol, cherry-anise,cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon,lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint,etc.

Sweetening agents that can be used in the present invention include, forexample, acesulfame potassium (acesulfame K), alitame, aspartame,cyclamate, cylamate, dextrose, isomalt, MagnaSweet®, maltitol, mannitol,neohesperidine DC, neotame, Prosweet® Powder, saccharin, sorbitol,stevia, sucralose, sucrose, tagatose, thaumatin, xylitol, and the like.

The foregoing excipients can have multiple roles as is known in the art.For example, starch can serve as a filler as well as a disintegrant. Theclassification of excipients above is not to be construed as limiting inany manner.

Pharmaceutical Dosage Forms

Compositions of the present invention can be formulated as solid, liquidor semi-solid dosage forms. In one embodiment, such compositions are inthe form of discrete dose units or dosage units. The terms “dose unit”and/or “dosage unit” herein refer to a portion of a pharmaceuticalcomposition that contains an amount of a therapeutic agent suitable fora single administration to provide a therapeutic effect. Such dosageunits may be administered one to a small plurality (i.e. 1 to about 4)of times per day, or as many times as needed to elicit a therapeuticresponse. A particular dosage form can be selected to accommodate anydesired frequency of administration to achieve a specified daily dose.Typically one dose unit, or a small plurality (i.e. up to about 4) ofdose units, provides a sufficient amount of the active drug (e.g.benzimidazole moiety) to result in the desired response or effect.

Alternatively, compositions of the invention can also be formulated forrectal, topical, or parenteral (e.g. subcutaneous, intramuscular,intravenous and intradermal or infusion) delivery.

In one embodiment, compositions of the invention are suitable for rapidonset of therapeutic effect, particularly with respect to the PPIcomponent. In another embodiment, upon oral administration of acomposition of the invention to a subject, at least a therapeuticallyeffective amount of the PPI is available for absorption in the stomachof the subject. As discussed above, most commercially available PPIsrequire enteric coating to prevent exposure of the PPI togastrointestinal fluids (and consequent drug degradation) by way of pHdependent coatings. Such coating, in turn, prevents rapid PPI absorptionand therapeutic onset of action. Compositions of the present invention,by contrast, do not require enteric coating to maintain drug stabilityin gastrointestinal fluids and thereby provide for rapid absorption andonset of therapeutic effect. In fact, in one embodiment, a compositioncomprises at least a therapeutically effective amount of PPI that is notenteric coated.

In one embodiment, a single dosage unit, be it solid or liquid,comprises a therapeutically effective amount or a therapeutically and/orprophylactically effective amount of PPI. The term “therapeuticallyeffective amount” or “therapeutically and/or prophylactically effectiveamount” as used herein refers to an amount of compound or agent that issufficient to elicit the required or desired therapeutic and/orprophylactic response, as the particular treatment context may require.

It will be understood that a therapeutically and/or prophylacticallyeffective amount of a drug for a subject is dependent inter alia on thebody weight of the subject. A “subject” herein to which a therapeuticagent or composition thereof can be administered includes a humansubject of either sex and of any age, and also includes any nonhumananimal, particularly a domestic or companion animal, illustratively acat, dog or a horse.

Solid Dosage Forms

In some embodiments, compositions of the invention are in the form ofsolid dosage forms or units. Non-limiting examples of suitable soliddosage forms include tablets (e.g. suspension tablets, bite suspensiontablets, rapid dispersion tablets, chewable tablets, effervescenttablets, bilayer tablets, etc), caplets, capsules (e.g. a soft or a hardgelatin capsule), powder (e.g. a packaged powder, a dispensable powderor an effervescent powder), lozenges, sachets, cachets, troches,pellets, granules, microgranules, encapsulated microgranules, powderaerosol formulations, or any other solid dosage form reasonably adaptedfor oral administration.

Tablets are an illustrative dosage form for compositions of theinvention. Tablets can be prepared according to any of the manyrelevant, well known pharmacy techniques. In one embodiment, tablets orother solid dosage forms can be prepared by processes that employ one ora combination of methods including, without limitation, (1) dry mixing,(2) direct compression, (3) milling, (4) dry or non-aqueous granulation,(5) wet granulation, or (6) fusion.

The individual steps in the wet granulation process of tabletpreparation typically include milling and sieving of the ingredients,dry powder mixing, wet massing, granulation and final grinding. Drygranulation involves compressing a powder mixture into a rough tablet or“slug” on a heavy-duty rotary tablet press. The slugs are then broken upinto granular particles by a grinding operation, usually by passagethrough an oscillation granulator. The individual steps include mixingof the powders, compressing (slugging) and grinding (slug reduction orgranulation). Typically, no wet binder or moisture is involved in any ofthe steps.

In another embodiment, solid dosage forms such as tablets can beprepared by mixing a PPI with at least one buffering agent as describedherein above and, if desired, with one or more optional pharmaceuticalexcipient to form a substantially homogeneous preformulation blend. Thepreformulation blend can then be subdivided and optionally furtherprocessed (e.g. compressed, encapsulated, packaged, dispersed, etc.)into any desired dosage forms.

Compressed tablets can be prepared by compacting a powder or granulationcomposition of the invention. The term “compressed tablet” generallyrefers to a plain, uncoated tablet suitable for oral ingestion, preparedby a single compression or by pre-compaction tapping followed by a finalcompression. Tablets of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of improvedhandling or storage characteristics. Preferably, however, any suchcoating will be selected so as to not substantially delay onset oftherapeutic effect of a composition of the invention upon administrationto a subject. The term “suspension tablet” as used herein refers to acompressed tablet that rapidly disintegrates after placement in water.

In one embodiment, a composition of the invention comprises amulti-layer tablet having a core comprising a proton pump inhibitor; thecore is substantially or completely surrounded by the buffering agent.In one such embodiment, the buffering agent layer completely surroundsthe core. In another embodiment, the buffering agent layer partiallysurrounds the core. In yet another embodiment, the buffering agent layeris in contact with a portion of or with all of the surface area of thecore.

In another embodiment, one or more intermediate layers exists in betweenthe core and the buffering agent. The intermediate layers can compriseany pharmaceutically acceptable material, preferably inert and non-pHsensitive coating materials such as polymer based coatings.

In still another embodiment, compositions of the invention can bemicroencapsulated, for example as is described in U.S. PatentPublication No. 2005/0037070, hereby incorporated by reference herein inits entirety.

In another embodiment, a composition of the invention comprises a protonpump inhibitor and a buffering agent mixed together in powder form andoptionally filled into a capsule, for example a hard or soft gelatin orHPMC capsule.

Liquid Dosage Forms

In another embodiment of the invention, compositions can be in the formof liquid dosage forms or units. Non-limiting examples of suitableliquid dosage forms include solutions, suspension, elixirs, syrups,liquid aerosol formulations, etc.

In one embodiment, a liquid composition comprising water, PPI and abuffering agent can be prepared. In another embodiment, compositions ofthe invention are in the form of a powder for suspension that can besuspended in a liquid vehicle prior to administration to a subject.While the powder for suspension itself, can be a solid dosage form ofthe present invention, the powder dispersed in liquid also comprises aliquid embodiment of the invention.

Generally, a liquid composition of PPI (without a buffering agent) wouldexhibit a very short period of stability, even when maintained underrefrigerated conditions. This is particularly inconvenient in thehospital setting as fresh batches of suspension are continuallyrequired.

Suspension compositions of the invention comprise at least one PPI, abuffering agent, a liquid media (e.g. water, de-ionized water, etc.) andone or more optional pharmaceutical excipients. Such compositions, uponstorage in a closed container maintained at either room temperature,refrigerated (e.g. about 5-10° C.) temperature, or freezing temperaturefor a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months,exhibit at least about 90%, at least about 92.5%, at least about 95%, orat least about 97.5% of the original PPI present therein.

Storage Stability

In one embodiment, compositions of the invention are in the form of apowder for suspension that is ultimately to be suspended in a liquidvehicle prior to administration to a subject. Liquid compositionscomprising an acid labile PPI suspended in a liquid vehicle, withoutmore, would typically exhibit short periods of stability, even whenmaintained under refrigerated conditions. This is particularlyinconvenient in the hospital setting as fresh batches of suspension arecontinually required. Suspension compositions of the invention arebelieved to exhibit improve storage stability.

Illustrative suspension compositions of the invention comprise at leastone PPI, at least one buffering agent, vitamin B₁₂, water, and one ormore optional pharmaceutical excipients. Such compositions, upon storagein a closed container maintained at room temperature, refrigerated (e.g.about 5 to about 5-10° C.) temperature, or frozen for a period of about1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, preferably exhibit atleast about 90%, more preferably at least about 92.5%, still morepreferably at least about 95%, and yet more preferably at least about97.5% of the proton pump inhibitor present therein.

Parietal Cell Activators

In one embodiment, a composition of the present invention can furtherinclude one or more parietal cell activators. Parietal cell activatorsare particularly preferred where the benzimidazole moiety is a PPI.Parietal cell activators such as chocolate, calcium and sodiumbicarbonate and other alkaline substances stimulate the parietal cellsand enhance the pharmacologic activity of the PPI administered. For thepurposes of this application, “parietal cell activator” or “activator”shall mean any compound or mixture of compounds possessing suchstimulatory effect including, but not limited to, chocolate, sodiumbicarbonate, calcium (for example, calcium carbonate, calcium gluconate,calcium hydroxide, calcium acetate and calcium glycerophosphate),peppermint oil, spearmint oil, coffee, tea and colas (even ifdecaffeinated), caffeine, theophylline, theobromine, and amino acids(particularly aromatic amino acids such as phenylalanine and tryptophan)and combinations thereof.

Parietal cell activators, if desired, are typically present in acomposition of the invention in an amount sufficient to produce thedesired stimulatory effect without causing untoward side effects topatients. For example, chocolate, as raw cocoa, is administered in anamount of about 5 mg to 2.5 g per 20 mg dose of omeprazole (orequivalent pharmacologic dose of another proton pump inhibiting agent).The dose of activator administered to a subject, for example, a human,in the context of the present invention should be sufficient to resultin enhanced effect of a PPI over a desired time frame.

Illustratively, the approximate effective ranges for various parietalcell activators per 20 mg dose of omeprazole (or equivalent dose ofother PPI) include, Chocolate (raw cocoa)—5 mg to 2.5 g; Sodiumbicarbonate—7 mEq to 25 mEq; Calcium carbonate—1 mg to 1.5 g; Calciumgluconate—1 mg to 1.5 g; Calcium lactate—1 mg to 1.5 g; Calciumhydroxide—1 mg to 1.5 g; Calcium acetate—0.5 mg to 1.5 g; Calciumglycerophosphate—0.5 mg to 1.5 g; Peppermint oil—(powdered form) 1 mg to1 g; Spearmint oil—(powdered form) 1 mg to 1 g; Coffee—ml to 240 ml;Tea—20 ml to 240 ml; Cola—20 ml to 240 ml; Caffeine—0.5 mg to 1.5 g;Theophylline—0.5 mg to 1.5 g; Theobromine—0.5 mg to 1.5 g;Phenylalanine—0.5 mg to 1.5 g; and Tryptophan—0.5 mg to 1.5 g.

Administration

Compositions of the present invention are useful for treating and/orpreventing, inter alia, gastrointestinal disorders and, in particular,acid related gastrointestinal disorders. The phrase “acid relatedgastrointestinal disorder” or “acid related gastrointestinal disease”refers generally to a disease or disorder that occurs due to animbalance between acid and pepsin production on the one hand, so-calledaggressive factors, and mucous, bicarbonate, and prostaglandinproduction on the other hand, so-called defensive factors.

The term “treat” or “treatment” as used herein refers to any treatmentof a disorder or disease associated with a gastrointestinal disorder,and includes, but is not limited to, preventing the disorder or diseasefrom occurring in a subject that may be predisposed to the disorder ordisease but has not yet been diagnosed as having the disorder ordisease; inhibiting the disorder or disease, for example, arresting thedevelopment of the disorder or disease; relieving the disorder ordisease, for example, causing regression of the disorder or disease; orrelieving the condition caused by the disease or disorder, for example,stopping the symptoms of the disease or disorder.

The term “prevent” or “prevention,” in relation to a gastrointestinaldisorder or disease, means preventing the onset of gastrointestinaldisorder or disease development if none had occurred, or preventingfurther gastrointestinal disorder or disease development if thegastrointestinal disorder or disease was already present.

In mammals gastrointestinal disorders include, but are not limited to,duodenal ulcer, gastric ulcer, acid dyspepsia, gastroesophageal refluxdisease (GERD), severe erosive esophagitis, poorly responsivesymptomatic gastroesophageal reflux disease, (acid reflux), heartburn,nighttime heartburn symptoms, nocturnal acid breakthrough (NAB), andgastrointestinal pathological hypersecretory conditions such asZollinger Ellison Syndrome. Illustrative acid-related gastrointestinaldisorders including duodenal ulcer disease, gastric ulcer disease,gastroesophageal reflux disease (GERD), erosive esophagitis, poorlyresponsive symptomatic gastroesophageal reflux disease (acid reflux),pathological gastrointestinal hypersecretory disease, Zollinger EllisonSyndrome, acid dyspepsia, heartburn, and/or NSAID induced ulcer.

Where the disorder is heartburn, the heartburn can be meal-related orinduced, sleep-related or induced, and/or nighttime-related or inducedheartburn. Sleep-related heartburn and/or nighttime-related heartburncan be caused, for example, by breakthrough gastritis betweenconventional doses of a therapeutic agent, such as while sleeping or inthe early morning hours after a night's sleep. Treatment of theseconditions is accomplished by administering to a subject agastrointestinal-disorder-effective amount (or atherapeutically-effective amount) of a pharmaceutical compositionaccording to the present invention. A subject may be experiencing one ormore of the above conditions or disorders or related symptoms.

Compositions of the invention can be administered to a subject at anysuitable time, for example upon waking, prior to a meal, during the day,or at night time (e.g. before bed). In one embodiment, a composition ofthe invention is useful for treating and/or preventing nighttimeheartburn or nighttime heartburn symptoms, nocturnal acid breakthrough(NAB), and/or for providing nighttime pH control. NAB herein refers tointragastric pH less than 4 for more than 1 hour in the overnightperiod.

In another embodiment, a composition of the invention is administered toa subject between about 6:00 pm and about 1:00 am, about 7:00 pm andabout 1:00 am, about 8:00 pm and about 12:00 am, about 8:00 pm and about11: pm, about 8:00 pm and about 10:30 pm, or about 9:00 pm and about10:30 pm, for example at about 9:00 pm, 9:15 pm, 9:30 pm, 9:45 pm, 10:00pm, 10:15 pm or 10:30 pm.

In another embodiment, a composition of the invention is administered toa subject within about 3 hours before or after the subject has eatendinner, within about 2 hours before or after the subject has eatendinner, within about 1 hour before or after the subject has eaten dinneror within about 30 minutes before or after the subject has eaten dinner.

In another embodiment, a composition of the invention is administered toa subject at such a time to result in a blood serum concentration of theproton pump inhibitor of at least about 0.1 micromolar, at least about0.2 micromolar, at least about 0.3 micromolar, at least about 0.4micromolar, at least about 0.5 micromolar, at least about 0.6micromolar, at least about 0.7 micromolar, at least about 0.8micromolar, at least about 0.9 micromolar that occurs at any time duringthe subject's typical period of nocturnal acid breakthrough, for examplethe subject's next typical period of nocturnal acid breakthroughfollowing administration.

The term “the subject's typical period of nocturnal acid breakthrough”refers to a period of time at night during which a subject tends toexperience intragastric pH not greater than 4 for a continuous period ofabout one hour. This can be determined, for example, by measuring asubject's intragastric pH for 1 to 3 nights and calculating thebeginning and ending times (of pH less than 4), or the average beginningand ending times if pH is measured during more than 1 night. Forexample, if a subject experiences nocturnal acid breakthrough on a firstmeasured day starting at 1:00 am and ending at 4:00 am, and on a secondmeasured day that subject experiences nocturnal acid breakthroughstarting at 2:00 am and ending at 5:00 am, the subject's typical periodof nocturnal acid breakthrough could be characterized as 1:30 am to 4:30am. Thus, a composition of the invention could be administered to thesubject at such a time so as to provide a blood serum concentration ofthe proton pump inhibitor of at least about 0.1 micromolar, at leastabout 0.2 micromolar, at least about 0.3 micromolar, at least about 0.4micromolar, at least about 0.5 micromolar, at least about 0.6micromolar, at least about 0.7 micromolar, at least about 0.8micromolar, or at least about 0.9 micromolar at any time during theperiod of about 12:00 am to about 6:00 am, about 12:30 am to about 5:30am, about 1:00 am to about 5:00 am, or about 2:00 am to about 4:00 amfollowing administration.

In another embodiment, a composition of the invention is administered toa subject at such a time to result in a blood serum concentration of theproton pump inhibitor of at least about 0.1 micromolar, at least about0.2 micromolar, at least about 0.3 micromolar, at least about 0.4micromolar, at least about 0.5 micromolar, at least about 0.6micromolar, at least about 0.7 micromolar, at least about 0.8micromolar, at least about 0.9 micromolar or at least about 1 micromolarcontinuously throughout the subject's typical period of nocturnal acidbreakthrough, for example the subject's next typical period of nocturnalacid breakthrough after administration.

In another embodiment, a composition of the invention is administered toa subject at such a time to result in a blood serum concentration of theproton pump inhibitor of at least about 0.1 micromolar, at least about0.2 micromolar, at least about 0.3 micromolar, at least about 0.4micromolar, at least about 0.5 micromolar, at least about 0.6micromolar, at least about 0.7 micromolar, at least about 0.8micromolar, at least about 0.9 micromolar, or at least about 1micromolar at any time point during the period of about 12:00 am toabout 6:00 am, about 12:30 am to about 5:30 am, about 1:00 am to about5:00 am, or about 2:00 am to about 4:00 am following administration.

The term “following administration” in the context of timing ofadministration means the next relevant time period after administration.For example, if a composition of the invention is to be administered toa subject at such a time to result in a blood serum concentration of theproton pump inhibitor of about 0.1 micromolar to about 5 micromolar atany time point from about 12:00 am to about 6:00 am followingadministration, that refers to the next 12:00 am to 6:00 am periodfollowing administration. If the composition was administered at 10:00pm on Day 1, the period of about 12:00 am to about 6:00 am followingadministration refers to 12:0 am to about 6:00 am on the day immediatelyfollowing Day 1.

In another embodiment, a composition of the invention is administered toa subject at such a time to result in a blood serum concentration of theproton pump inhibitor of at least about 0.1 micromolar, at least about0.2 micromolar, at least about 0.3 micromolar, at least about 0.4micromolar, at least about 0.5 micromolar, at least about 0.6micromolar, at least about 0.7 micromolar, at least about 0.8micromolar, at least about 0.9 micromolar or at least about 1 micromolarcontinuously from about 12:00 am to about 6:00 am, from about 12:30 amto about 5:30 am, from about 1:00 am to about 5:00 am, or from about2:00 am to about 4:00 am following administration.

In another embodiment, a composition of the invention is administered toa subject at such a time to result in a blood serum concentration of theproton pump inhibitor of about 0.1 micromolar to about 5 micromolar,about 0.2 micromolar to about 2.5 micromolar, or about 0.3 micromolar toabout 2 micromolar continuously from about 12:00 am to about 6:00 am,from about 12:30 am to about 5:30 am, from about 1:00 am to about 5:00am, or from about 2:00 am to about 4:00 am following administration.

In another embodiment, a composition of the invention is administered toa subject at such a time to result in a blood serum concentration of theproton pump inhibitor of about 0.1 micromolar to about 5 micromolar,about 0.2 micromolar to about 2.5 micromolar, or about 0.3 micromolar toabout 2 micromolar from about 12:00 am to about 6:00 am, from about12:30 am to about 5:30 am, at any time during the period of about 1:00am to about 5:00 am, or from about 2:00 am to about 4:00 am followingadministration.

In still another embodiment, a composition of the invention isadministered to a subject at such a time to result in a C_(max) of theproton pump inhibitor that occurs during the subject's typical period ofnocturnal acid breakthrough, for example during the subject's typicalperiod of nocturnal acid breakthrough following administration.

In another embodiment, a composition of the invention is administered toa subject at such a time to result in a C_(max) of the proton pumpinhibitor that occurs about 0.1 to about 5 hours, about 0.1 to about 4hours, about 0.1 to about 3 hours, or about 0.1 to about 2 hours beforethe subject's typical period of nocturnal acid breakthrough, for exampleduring the subject's typical period of nocturnal acid breakthroughfollowing administration.

Castell, Donald et al., Zegerid Oral Suspension is More Effective thanPantoprazole (Protonix) Delayed-Release Capsules in Reducing NighttimeGastric Acidity in GERD Patients, American Journal of Gastroenterology,Vol 99, No. 10 S40 is hereby incorporated by reference herein in itsentirety.

Compositions of the invention are to be administered and dosed inaccordance with good medical practice, taking into account the clinicalcondition of the individual patient, the site and method ofadministration, scheduling of administration and other factors known tomedical practitioners. In human therapy, it is important to provide adosage form that delivers the required therapeutic amount of the drug invivo, and renders the drug bioavailable in a rapid manner. In additionto the dosage forms described herein, the dosage forms described byPhillips et al. in U.S. Pat. No. 6,489,346 are incorporated herein byreference.

The percent of intact drug that is absorbed into the bloodstream is notnarrowly critical, as long as a therapeutic-disorder-effective amount,for example a gastrointestinal-disorder-effective amount of a protonpump inhibiting agent, is absorbed following administration of thepharmaceutical composition to a subject. It will be understood that theamount of proton pump inhibiting agent and/or antacid that isadministered to a subject is dependent on various factors including thesex, general health, diet, and/or body weight of the subject.

Illustratively, when administering a PPI to a young child or a smallanimal, such as a dog, a relatively low amount of the proton pumpinhibitor, e.g., about 1 mg to about 30 mg, will often provide bloodserum concentrations consistent with therapeutic effectiveness. Wherethe subject is an adult human or a large animal, such as a horse,achievement of a therapeutically effective blood serum concentration mayrequire larger dosage units, for example about 10 mg, about 15 mg, about20 mg, about 30 mg, about 40 mg, about 80 mg, or about 120 mg dose foran adult human, or about 150 mg, or about 200 mg, or about 400 mg, orabout 800 mg, or about 1000 mg dose, or about 1500 mg dose, or about2000 mg dose, or about 2500 mg dose, or about 3000 mg dose, or about3200 mg dose, or about 3500 mg dose for an adult horse.

In various other embodiments of the present invention, the amount ofproton pump inhibitor administered to a subject is about 1-2 mg/Kg ofbody weight, illustratively about 0.5 mg/Kg of body weight, about 1mg/Kg of body weight, about 1.5 mg/Kg of body weight, or about 2 mg/Kgof body weight.

Treatment dosages generally may be titrated to optimize safety andefficacy. Typically, dosage-effect relationships from in vitro and/or invivo tests initially can provide useful guidance on the proper doses forsubject administration. Studies in animal models generally may be usedfor guidance regarding effective dosages for treatment ofgastrointestinal disorders or diseases in accordance with the presentinvention. In terms of treatment protocols, it should be appreciatedthat the dosage to be administered will depend on several factors,including the particular agent that is administered, the route chosenfor administration, and the condition of the particular subject.

In another embodiment of the present invention, the composition isadministered to a subject in an amount sufficient to achieve ameasurable serum concentration of a non-acid degraded or non-acidreacted proton pump inhibitor greater than about 100 ng/ml within about30 minutes or about 15 minutes or about 10 minutes after administrationof the composition.

In another embodiment of the present invention, the composition isadministered to a subject in an amount sufficient to achieve ameasurable serum concentration of the proton pump inhibitor greater thanabout 150 ng/ml within about 15 minutes and to maintain a serumconcentration of the proton pump inhibitor of greater than about 150ng/ml from about 15 minutes to about 1 hour after administration of thecomposition. In yet another embodiment of the present invention, thecomposition is administered to the subject in an amount sufficient toachieve a measurable serum concentration of the proton pump inhibitorgreater than about 250 ng/ml within about 15 minutes and to maintain aserum concentration of the proton pump inhibiting agent of greater thanabout 150 ng/ml from about 15 minutes to about 1 hour afteradministration of the composition.

In another embodiment of the present invention, the composition isadministered to the subject in an amount sufficient to achieve ameasurable serum concentration of the proton pump inhibitor greater thanabout 350 ng/ml within about 15 minutes and to maintain a serumconcentration of the proton pump inhibitor of greater than about 150ng/ml from about 15 minutes to about 1 hour after administration of thecomposition. In another embodiment, the composition is administered tothe subject in an amount sufficient to achieve a measurable serumconcentration of the proton pump inhibiting agent greater than about 450ng/ml within about 15 minutes and to maintain a serum concentration ofthe proton pump inhibiting agent of greater than about 150 ng/ml fromabout 15 minutes to about 1 hour after administration of thecomposition.

In another embodiment, the composition is administered to the subject inan amount sufficient to achieve a measurable serum concentration of theproton pump inhibitor greater than about 150 ng/ml within about 30minutes and to maintain a serum concentration of the proton pumpinhibitor of greater than about 150 ng/ml from about 30 minutes to about1 hour after administration of the composition. In yet anotherembodiment of the present invention, the composition is administered tothe subject in an amount to achieve a measurable serum concentration ofthe proton pump inhibitor greater than about 250 ng/ml within about 30minutes and to maintain a serum concentration of the proton pumpinhibitor of greater than about 150 ng/ml from about 30 minutes to about1 hour after administration of the composition. In another embodiment ofthe present invention, the composition is administered to the subject inan amount sufficient to achieve a measurable serum concentration of theproton pump inhibitor greater than about 350 ng/ml within about 30minutes and to maintain a serum concentration of the proton pumpinhibitor of greater than about 150 ng/ml from about 30 minutes to about1 hour after administration of the composition. In another embodiment ofthe present invention, the composition is administered to the subject inan amount sufficient to achieve a measurable serum concentration of theproton pump inhibitor greater than about 450 ng/ml within about 30minutes and to maintain a serum concentration of the proton pumpinhibiting agent of greater than about 150 ng/ml from about 30 minutesto about 1 hour after administration of the composition.

In still another embodiment of the present invention, the composition isadministered to the subject in an amount sufficient to achieve ameasurable serum concentration of a non-acid degraded or non-acidreacted proton pump inhibitor greater than about 500 ng/ml within about1 hour after administration of the composition. In yet anotherembodiment of the present invention, the composition is administered tothe subject in an amount to achieve a measurable serum concentration ofa non-acid degraded or non-acid reacted proton pump inhibitor greaterthan about 300 ng/ml within about 45 minutes after administration of thecomposition.

Contemplated compositions of the present invention provide a therapeuticeffect as proton pump inhibiting agent medications over an interval ofabout 5 minutes to about 24 hours after administration, enabling, forexample, once-a-day, twice-a-day, or three times a day administration ifdesired.

In another embodiment, upon oral administration of a composition of theinvention to a plurality of fasted human subjects, the subjects exhibitan average T_(max) of PPI within about 30 seconds to about 90 minutes,within about 1 minute to about 80 minutes, within about 5 minutes toabout 60 minutes, within about 10 minutes to about 50 minutes, or withinabout 15 minutes to about 45 minutes.

In still another embodiment, upon administration of a composition of theinvention to a plurality of fasted human subjects, the subjects exhibitan average plasma concentration of the PPI of at least about 0.1 μg/ml,at least about 0.15 μg/ml, at least about 0.2 μg/ml, at least about 0.3μg/ml, at least about 0.4 μg/ml, at least about 0.5 μg/ml, at leastabout 0.6 μg/ml, at least about 0.7 μg/ml, at least about 0.8 μg/ml, atleast about 0.9 μg/ml, at least about 1 μg/ml, at least about 1.5 μg/ml,or at least about 2.0 μg/ml at any time within about 90 minutes, withinabout 75 minutes, within about 60 minutes, within about 55 minutes,within about 50 minutes, within about 45 minutes, within about 40minutes, within about 35 minutes, within about 30 minutes, within about25 minutes, within about 20 minutes, within about 17 minutes, withinabout 15 minutes, within about 12 minutes, or within about 10 minutesafter administration.

In yet another embodiment, upon administration of a composition of theinvention to a plurality of fasted human subjects, the subjects exhibita plasma concentration of PPI of at least about 0.1 μg/ml, at leastabout 0.15 μg/ml, at least about 0.2 μg/ml, at least about 0.3 μg/ml, atleast about 0.4 μg/ml, at least about 0.5 μg/ml, at least about 0.6μg/ml, at least about 0.7 μg/ml, at least about 0.8 μg/ml, at leastabout 0.9 μg/ml, at least about 1.0 μg/ml, at least about 1.5 μg/ml orat least about 2.0 μg/ml, maintained from at latest about 15 minutes toat earliest about 60 minutes after administration, preferably at latestabout 15 minutes after administration to at earliest about 90 minutesafter administration, more preferably at latest about 15 minutes to atearliest about 120 minutes after administration, and still morepreferably at latest about 15 minutes to at earliest about 180 minutesafter administration.

In another embodiment, upon administration of a composition of theinvention to a plurality of fasted human subjects, the subjects exhibitat least one of: a mean C_(max) of PPI of about 500 μg/ml to about 2000μg/ml, about 600 μg/ml to about 1900 μg/ml, or about 700 ng/ml to about1800 μg/ml; a mean T_(max) of PPI of about 0.15 to about 2 hours, about0.25 to about 1.75 hours, or about 0.3 hours to about 1 hour; and/or amean AUC_((0-inf)) of PPI of about 1000 to about 3000 g*hr/ml, about1500 to about 2700 μg*hr/ml, or about 1700 to about 2500 μg*hr/ml.

In another embodiment, upon administration of a composition of theinvention to a plurality of fasted adult human subjects, the subjectsexhibit: a mean C_(max) of PPI of about 500 μg/ml to about 2000 μg/ml,about 600 μg/ml to about 1900 μg/ml, or about 700 μg/ml to about 1800μg/ml; a mean T_(max) of PPI of about 0.15 to about 2 hours, about 0.25to about 1.75 hours, or about 0.3 hours to about 1 hour; and a meanAUC_((0-inf)) of PPI of about 1000 to about 3000 ng*hr/ml, about 1500 toabout 2700 ng*hr/ml, or about 1700 to about 2500 ng*hr/ml.

Those skilled in the art will readily appreciate that numerous otherembodiments, modifications and equivalents are contemplated andencompassed by the disclosure of the present invention.

All U.S. patents and published U.S. patent applications listed hereinare hereby incorporated by reference in their entirety. All patents,patent applications and publications referenced herein are herebyincorporated by reference herein to the fullest extent allowed under thelaw.

EXAMPLES Example 1

Enteric coated pantoprazole and an immediate release omeprazoleformulation were compared in a clinical study. Thirty-two patients withnocturnal GERD symptoms were enrolled in a crossover trial; subjectswere provided 40 mg of enteric coated pantoprazole (Protonix®) given at2200 hours (bedtime) on Day 1 and prior to dinner on Days 2-6 or 40 mgof a non-enteric coated omeprazole suspension (Zegerid™) given at 2200hours on Days 1-6. On Day 7, both PPIs were given 1 hour prior tobreakfast and at 2200 hours. Continuous 24-hour gastric pH monitoring(Medtronic) was performed on Days 1, 6, and 7. Median gastric pH,percent of time gastric pH was less than 4, and the proportion ofpatients with “nocturnal acid breakthrough” (NAB) (>1 hr of continuouspH<4) were determined for the nighttime period (2200-0600 hours).

Nighttime median gastric pH on Day 6 is shown below. For this 8-hrperiod, median time that pH was >4 was greater for Zegerid™ (55%) thanfor Protonix® (27%) (p<0.001); median pH was 4.7 for Zegerid™ and 2.0for Protonix® (p<0.001). Furthermore, NAB occurred in fewerZegerid™-treated patients (17/32) than Protonix®-treated patients(25/32) (p=0.005). For the 8-hr nighttime period after twice-dailydosing, median % time that pH was >4 was greater for Zegerid™ (40 mg and20 mg) than for Protonix® (92% vs. 37% and 79% vs. 31%, p<0.001,respectively). Median pH was also higher for Zegerid™ (40 mg and 20 mg)than for Protonix® (6.5 vs. 1.5 and 5.8 vs. 1.9, p<0.001, respectively).NAB occurred in fewer Zegerid™-treated patients than Protonix®-treatedpatients (2/17 vs. 12/17 and 7/15 vs. 12/15, p<0.025, respectively). Theabove example is as described in Castell., Donald et al., Zegerid OralSuspension is More Effective than Pantoprazole (Protonix)Delayed-Release Capsules in Reducing Nighttime Gastric Acidity in GERDPatients, American Journal of Gastroenterology, Vol 99, No. 10 S40.

Example 2

Seventeen healthy subjects were enrolled in an open-label trial. Single20-mg doses of Zegerid™ suspension (Santarus, San Diego) were given 1 hrprior to breakfast (qAM) for 7 days. On Day 8, the 20-mg suspension wasgiven b.i.d.: at 0830 hrs (1 hr prior to a standardized high-fatbreakfast) and at 2200 hrs (bedtime). On Days 7 and 8, standardizedlunch and dinner were given at 1300 and 1800 hrs. Gastric pH wascontinuously monitored (Medtronic) for 24 hrs following the morningdoses on Days 7 and 8. The percent time pH was >4 was assessed for the8-hr nighttime period (2200-0600 hrs) and for the 24-hr period followingthe morning dose. The proportion of subjects with “nocturnal acidbreakthrough” (NAB) (>1 hr of continuous pH<4) was assessed for the 8-hrnighttime period.

After the bedtime dose, Zegerid™ 20 mg abruptly raised the gastric pHand sustained this effect for approximately 8 hrs. The median % time pHwas >4 was greater for b.i.d dosing (87%) than for qAM dosing (39%)(p<0.001). NAB occurred in fewer subjects dosed b.i.d. (5/17 [29%]) thandosed qAM (13/17 [76%]) (p=0.005).

1. A method for treating and/or preventing nocturnal acid breakthroughin a subject in need thereof, the method comprising: administering tothe subject a solid pharmaceutical composition comprising an acid labileproton pump inhibitor and a buffering agent, wherein: (a) the protonpump inhibitor is not enteric coated; (b) the proton pump inhibitor ispresent in the composition in an amount of about 5 mg to about 60 mg;(c) the buffering agent is present in the composition in an amount ofabout 200 mg to about 3500 mg; and (d) the administration step isperformed between about 8:00 pm and about 12:00 am, inclusive.
 2. Themethod of claim 1, wherein the administration step is performed betweenabout 9:00 pm and about 12:00 am, inclusive.
 3. The method of claim 1,wherein the administration step is performed between about 9:30 pm andabout 11:30 pm, inclusive.
 4. The method of claim 1 wherein the protonpump inhibitor is of Formula (I):

wherein R¹ is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy,carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy which isoptionally fluorinated, hydroxyalkyl, trifluoromethyl, acyl,carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, oralkylsulfinyl; R² is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino,aralkyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl; R³ and R⁵are the same or different and each is hydrogen, alkyl, alkoxy, amino, oralkoxyalkoxy; R⁴ is hydrogen, alkyl, alkoxy which may optionally befluorinated, or alkoxyalkoxy; Q is nitrogen, CH, or CR¹; W is nitrogen,CH, or CR¹; y is an integer of 0 through 4; and Z is nitrogen, CH, orCR¹; or a free base, salt, ester, hydrate, amide, enantiomer, isomer,tautomer, prodrug, polymorph, or derivative thereof.
 5. The method ofclaim 1 wherein the proton pump inhibitor is omeprazole, tenatoprazole,lansoprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole,leminoprazole and nepaprazole or a free base, a free acid, or a salt,hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug,or derivative of such compounds.
 6. The method of claim 1 wherein theproton pump inhibitor is omeprazole or lansoprazole.
 7. The method ofclaim 1 wherein the proton pump inhibitor is omeprazole.
 8. The methodof claim 1 wherein the proton pump inhibitor is present in an amount ofabout 10 mg to about 40 mg on a dry weight basis.
 9. The method of claim1 wherein the buffering agent is present in an amount of about 400 mg toabout 3000 mg on a dry weight basis.
 10. The method of claim 1 whereinthe buffering agent is present in an amount of about 500 mg to about2500 mg on a dry weight basis.
 11. The method of claim 1 wherein thecomposition further comprises at least one pharmaceutically acceptableexcipient.
 12. The method of claim 1 wherein the composition is a dosageform is selected from a tablet, a suspension tablet, a bite suspensiontablet, a rapid dispersion tablet, a chewable tablet, an effervescenttablet, a bilayer tablet, a caplet, a capsule, a powder, a lozenge, asachet, a cachet, a troche, a pellet, a granule and a microgranule. 13.A method for treating and/or preventing nocturnal acid breakthrough in asubject in need thereof, the method comprising: administering to thesubject a solid pharmaceutical composition comprising an acid labileproton pump inhibitor and a buffering agent, wherein: (a) the protonpump inhibitor is not enteric coated, (b) the proton pump inhibitor ispresent in the composition in an amount of about 5 mg to about 60 mg;(c) the buffering agent is present in the composition in an amount ofabout 200 mg to about 3500 mg; and (d) the administration step isperformed prior to 12:00 am and at such a time so as to result in ablood serum concentration of the proton pump inhibitor of at least about0.1 micromolar at any time point from about 12:00 am to about 6:00 amfollowing administration.
 14. The method of claim 13 wherein theadministration step is performed at such a time so as to result in ablood serum concentration of the proton pump inhibitor of at least about0.9 micromolar at any time point from about 1:00 am to about 5:00 amfollowing administration.
 15. The method of claim 13 wherein the protonpump inhibitor is of Formula (I):

wherein R¹ is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy,carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy which isoptionally fluorinated, hydroxyalkyl, trifluoromethyl, acyl,carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, oralkylsulfinyl; R² is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino,aralkyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl; R³ and R⁵are the same or different and each is hydrogen, alkyl, alkoxy, amino, oralkoxyalkoxy; R⁴ is hydrogen, alkyl, alkoxy which may optionally befluorinated, or alkoxyalkoxy; Q is nitrogen, CH, or CR¹; W is nitrogen,CH, or CR¹; y is an integer of 0 through 4; and Z is nitrogen, CH, orCR¹; or a free base, salt, ester, hydrate, amide, enantiomer, isomer,tautomer, prodrug, polymorph, or derivative thereof.
 16. The method ofclaim 13 wherein the proton pump inhibitor is omeprazole, tenatoprazole,lansoprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole,leminoprazole and nepaprazole or a free base, a free acid, or a salt,hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug,or derivative of such compounds.
 17. The method of claim 13 wherein theproton pump inhibitor is omeprazole or lansoprazole.
 18. The method ofclaim 13 wherein the proton pump inhibitor is omeprazole.
 19. The methodof claim 13 wherein the proton pump inhibitor is present in an amount ofabout 10 mg to about 40 mg on a dry weight basis.
 20. The method ofclaim 13 wherein the buffering agent is present in an amount of about400 mg to about 3000 mg on a dry weight basis.
 21. The method of claim13 wherein the buffering agent is present in an amount of about 500 mgto about 2500 mg on a dry weight basis.
 22. The method of claim 13wherein the composition further comprises at least one pharmaceuticallyacceptable excipient.
 23. The method of claim 13 wherein the compositionis a solid dosage form is selected from a tablet, a suspension tablet, abite suspension tablet, a rapid dispersion tablet, a chewable tablet, aneffervescent tablet, a bilayer tablet, a caplet, a capsule, a powder, alozenge, a sachet, a cachet, a troche, a pellet, a granule and amicrogranule.
 24. A method for treating and/or preventing nocturnal acidbreakthrough in a subject in need thereof, the method comprising:administering to the subject a solid pharmaceutical compositioncomprising an acid labile proton pump inhibitor and a buffering agent,wherein: (a) the proton pump inhibitor is not enteric coated; (b) theproton pump inhibitor is present in the composition in an amount ofabout 5 mg to about 60 mg; (c) the buffering agent is present in thecomposition in an amount of about 200 mg to about 3500 mg; and (d) theadministration step is performed prior to 2:00 am and at such a time soas to result in a blood serum concentration of the proton pump inhibitorof at least about 1 micromolar at any time point from about 2:00 am toabout 4:00 am following administration.
 25. A method for treating and/orpreventing nocturnal acid breakthrough in a subject in need thereof, themethod comprising the steps of: (a) determining the subject's typicalperiod of nocturnal acid breakthrough; and (b) providing the subjectwith a pharmaceutical composition comprising an acid labile, substitutedbenzimidazole H⁺, K⁺-ATPase proton pump inhibitor and a buffering agentat a time such that the subject exhibits a blood serum concentration ofthe proton pump inhibitor of at least about 0.1 micromolar at any timepoint during the subject's determined typical period of nocturnal acidbreakthrough.
 26. A method for treating and/or preventing nocturnal acidbreakthrough in a subject in need thereof, the method comprising thesteps of: (a) determining the subject's typical period of nocturnal acidbreakthrough; and (b) providing the subject with a pharmaceuticalcomposition comprising an acid labile, substituted benzimidazoleH⁺,K⁺-ATPase proton pump inhibitor and a buffering agent at a time suchthat the subject exhibits a blood serum concentration of the proton pumpinhibitor of at least about 1 micromolar at any time point during thesubject's determined typical period of nocturnal acid breakthrough.